Project Summary ? Overall Alcohol use disorders (AUDs) represent a major public health burden. Genetic risk factors contribute critically to susceptibility to AUDs and are likely a result of many variants each contributing modestly to risk. Genetic studies in animal models and humans have to date made slow progress in identifying individual genetic risk variants. However, modern high-throughput approaches such as genome-wide association studies or genomic expression profiling promise to rapidly increase the pool of potential candidate genes influencing AUDs. This proposal for a P50 Alcohol Research Center presents a novel and highly integrated overall design to focus on both gene discovery and functional interpretation for the genetics of AUDs. This application is a renewal of our currently funded P50 that supports the VCU Alcohol Research Center (VCU-ARC), which was first funded with a P20 Developmental Center grant in 2009. We have made significant progress over the past 4.5 years and here seek to both continue aspects of our prior directions but also to extend our work into new areas. Our approach continues to be innovative and significant due to three novel features: 1) A focus on gene networks contributing to AUD-related phenotypes and ethanol behaviors, rather than single genes; 2) A cross- species genetic and genomics analysis to validate candidate genes and networks affecting ethanol behaviors; and 3) A highly integrative Center design with rapid data sharing across projects through a cross-species analysis pipeline to provide ranked gene lists or networks for further experimental validation in the component projects. We request five years of support for five research projects and pilot grants for genetic studies in worms, flies, mice, rats and humans. Three projects will represent new areas of study, while two others will renew their overall strategy of current projects but with novel areas of investigation. Two projects will be in human genetics with state-of-the-art statistical approaches to leverage the power of large genome-wide association and exome sequencing studies on phenotypes significantly associated with AUDs. All projects will be supported by an Administrative Core, a Bioinformatics and Analysis Core and a Rodent Behavioral Core. The scientific work proposed in these projects and cores is clearly greater than the sum of its parts, due to the highly interactive structure of the VCU-ARC components. The VCU-ARC is well positioned to become a national resource, making major contributions to the advancement of our understanding of the etiology of AUDs and subsequently their prevention and treatment.